The gut microbe Bacteroides fragilis ameliorates renal fibrosis in mice

Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal fibrosis can therefore not be overemphasized. Here we show a novel protective role of Bacteroides fragilis (B. fragilis) in renal fibrosis in mice. We demonstrate decreased abundance of B. fragilis in the feces of CKD patients and unilateral ureteral obstruction (UUO) mice. Oral administration of live B. fragilis attenuates renal fibrosis in UUO and adenine mice models. Increased lipopolysaccharide (LPS) levels are decreased after B. fragilis administration. Results of metabolomics and proteomics studies show decreased level of 1,5-anhydroglucitol (1,5-AG), a substrate of SGLT2, which increases after B. fragilis administration via enhancement of renal SGLT2 expression. 1,5-AG is an agonist of TGR5 that attenuates renal fibrosis by inhibiting oxidative stress and inflammation. Madecassoside, a natural product found via in vitro screening promotes B. fragilis growth and remarkably ameliorates renal fibrosis. Our findings reveal the ameliorative role of B. fragilis in renal fibrosis via decreasing LPS and increasing 1,5-AG levels.


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Study protocol Cell lines were authenticated by short tandem repeat (STR) analysis.
HEK293 cell line was negative for mycoplasma. HK2 and HMC cell lines used tested negative for mycoplasma contamination prior to this study.
No commonly misidentified lines were used in this study.
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Mice were housed in pathogen-free and ventilated cages in a 12h light/dark cycle, with room temperature at 25±2°C and humidity between 40 and 60%. All mice used in this work were male. Eight-week-old ICR male mice (18 to 22g) were allowed free access to water and regular chow and their body weights taken every week.
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All animal treatments were approved by Animal Ethics Committee of China Pharmaceutical University (Nanjing, China). Animal testing and research conformed to all relevant ethical regulations.
The human research participants include CKD patients and healthy subjects. The age of participants are around 60 years old. The males are around 60%.
CKD patients with glomerular filtration rate (GFR) of less than 60 ml/min per 1.73 m2, or a marker of kidney damage, or both, for a duration of at least 3 months were recruited. Patients with acute kidney injury, liver disease, active vasculitis, gastrointestinal pathology or cancer were excluded from the study. Age-and sex-matched healthy subjects were also recruited. Patients were recruited at admission to the Affiliated Hospital of Nanjing University of Chinese Medicine, Renmin Hospital of Wuhan University, the Putuo People's Hospital, the Ningbo Hospital of Zhejiang University. Most eligible patients agreed to participation. As a consequence, self-selection bias is low.
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March 2021
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March 2021
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